Exfoliative toxin A (ETA), produced by Staphylococcus aureus, causes staphylococcal scalded skin syndrome (SSSS) and its more localized form, bullous impetigo. The crystal structure of ETA suggests that it is a serine protease with an inactive catalytic site which becomes activated when ETA binds a specific receptor. In pemphigus foliaceus autoantibodies that cause dysfunction of Dsg 1 cause blisters identical to those caused by ETA in the superficial epidermis of mouse and man. Therefore, we hypothesize that Dsg 1 specifically binds and activates ETA, which in turn cleaves the bound Dsg 1, resulting in blister formation. We propose that another staphylococcal toxin, exfoliative toxin B (ETB), that also causes bullous impetigo and SSSS, is also activated by, and cleaves, Dsg 1. Finally, we hypothesize that binding of ETA to Dsg 1 and/or cleavage of Dsg 1 by ETA might elicit an autoimmune response against Dsg 1, thus suggesting a mechanism for autoantibody production in PF patients. We have shown that ETA cleaves Dsg 1. Specific aim 1 will characterize this cleavage by determining if cleavage is dependent on Dsg 1 conformation, and by defining the site of cleavage and the domains of Dsg 1 needed for cleavage. Aim 2 will characterize binding of ETA to Dsg 1, and define the domains of each necessary. Aim 3 will determine, using Dsg 3 knockout and involucrin-Dsg 3 transgenic mice, if compensation by Dsg 3 can compensate for ETA-induced loss of function of Dsg 1, thereby explaining the sites of blister localization. Aim 4 contains studies designed to define the kinetics of Dsg 1 cleavage by ETA. Aim 5 will extend the results of the previous aims to include the mechanisms of action of ETB. The final aim will determine if patients with bullous impetigo and SSSS develop an antibody response against Dsg 1, if patients with pemphigus foliaceus have an enhanced immune response against ETA and ETB, and if mice injected with ETA develop an immune response against Dsg 1. These studies will provide insight regarding the molecular pathophysiology of a very common disease, bullous impetigo, and, for the first time, identify a potential trigger or exacerbating factor in a tissue-specific autoimmune disease, pemphigus.